The transmissible spongiform encephalopathies (TSEs or prion diseases)are fatal neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy and chronic wasting disease (CWD). We aim to gain a better understanding of the underlying mechansims of TSE diseases in order to develop effective diagnostic tests and treatments. The conversion of normal PrP (PrP-sen) to PrP-res, the abnormal form of prion protein (PrP) appears to underlie TSE transmission and pathogenesis. We have employed a number of different cell biological, biochemical, biophysical and in vivo experimental approaches to understand this basic conversion reaction and its implications for disease in humans and animals. [unreadable] [unreadable] During FY2008 we have 1) improved our ultrasensitive and relatively rapid prion assays based on prion-seeded conversion of cell-free conversion of full-length recombinant PrP, 2)compared strain-dependent ultrastructures of amyloid fibrils from scrapie-infected GPI anchorless PrP transgenic mice, 3) used nuclear magnetic resonance techniques to analyze the structure of the flexible amino-terminal domain of PrP when bound to PrP conversion inhibitors, 4) analyzed effects of phosphorothioate oligonucleotides on scrapie infectivity in tissues, 5) improved our understanding of the smallest and most infectious prion particles, and 6) assayed for any infectivity in products of PrP-res-seeded conversions of recombinant PrP-sen.